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Damaged mitochondria may be one of the earliest manifestations of Alzheimer's disease. Because oxidative phosphorylation is a primary source of neuronal energy, unlike glycolysis-dependent energy production in inflamed glia, mitochondrial respiration could provide a selective biomarker of neuronal deterioration in Alzheimer's disease. Here we used a recently developed positron emission tomography (PET) probe targeting mitochondrial complex I (MC-I), 18 F-BCPP-EF, to non-invasively visualize mitochondrial abnormalities in the brains of tau transgenic mice (rTg4510). Tauopathy and neuroinflammation were visualized by PET using a tau probe 11 C-PBB3 and a translocator protein probe, 18 F-FEBMP, respectively. A marked reduction in 18 F-BCPP-EF uptake was observed in hippocampal and forebrain regions of tau transgenic mice, colocalizing with regions of tauopathy, neuronal damage, and neuroinflammation. MC-I signals were highly correlated with atrophy assayed by magnetic resonance imaging, but negatively associated with inflammatory signals, indicating that neuronal metabolic signals measured by MC-I PET were robust to inflammatory interference. MC-I may be a useful imaging biomarker to detect neuronal damage and metabolic changes with minimal interference from concomitant glial hypermetabolism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Time courses of the redox status in the brains of mice after X-ray or carbon-ion beam irradiation were observed by magnetic resonance redox imaging (MRRI). The relationship between radiation-induced oxidative stress on the cerebral nervous system and the redox status in the brain was discussed. The mice were irradiated by 8-Gy X-ray or carbon-ion beam (C-beam) on their head under anesthesia. C-beam irradiation was performed at HIMAC (Heavy-Ion Medical Accelerator in Chiba, NIRS/QST, Chiba, Japan). MRRI measurements using a blood-brain-barrier-permeable nitroxyl contrast agent, MCP or TEMPOL, were performed using 7-T scanner at several different times, i.e., 5-10 h, 1, 2, 4, and 8 day(s) after irradiation. Decay rates of the nitroxyl-enhanced T 1 -weighted MR signals in the brains were estimated from MRRI data sets, and variation in the decay rates after irradiation was assessed. The variation in decay rates of MCP and TEMPOL after X-ray or C-beam irradiation was similar, but different variation patterns were observed between X-ray and C-beam. The apparent decay rate of both MCP and TEMPOL decreased due to the temporal reduction of blood flow in the brain several hours after X-ray and/or C-beam irradiation. After decreasing, the apparent decay rates of nitroxyl radicals in the brain gradually increased during the following days after X-ray irradiation or rapidly increased 1 day after C-beam irradiation. The sequential increase in nitroxyl decay rates may have been due to the oxidative atmosphere in the tissue due to ROS generation. X-ray and C-beam irradiation resulted in different redox responses, which may have been due to time-varying oxidative stress/injury, in the mouse brain. The C-beam irradiation effects were more acute and larger than those of X-ray irradiation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

MRI observations following in vivo administration of Mn 2+ [manganese (Mn)-enhanced MRI, MEMRI] have been used as an excellent morphological and functional MRI tool for in vivo preclinical studies. To detect brain three-dimensional (3D) microstructures, we improved the ex vivo MEMRI method for mouse brains after in vivo Mn administration and obtained high-resolution MRIs using a cryogenic radiofrequency (RF) coil. Male C57BL/6 mice ( n = 8) were injected with 50 mM MnCl 2 intravenously and MEMRIs of the brain were acquired in vivo after 24 h, followed by perfusion fixation with a 4% paraformaldehyde (PFA) solution. High-resolution 25-μm isotropic MRIs were successfully acquired from the extracted brain tissue and could identify the brain microstructures, especially in the hippocampus [the pyramidal cell layer through CA1-3 and the dentate gyrus (DG) granular layers (GLs)], cell layers of cerebellum, three sub-regions of the deep cerebellar nucleus, and white matter (WM) structures [e.g., the fasciculus retroflexus (fr) and optic tract in the thalamus]. The following technical conditions were also examined: (i) the longitudinal stability of Mn-enhanced ex vivo tissue after in vivo administration; and (ii) the effects of mixing glutaraldehyde (GA) with the fixative solution for the preservation of in vivo MEMRI contrast. Our results indicate that ex vivo MEMRI observations made shortly after fixation maintain the contrast observed in vivo . This research will be useful for non-destructive whole-brain pathological analysis.

Autosomal recessive primary microcephaly-5 (MCPH5) is characterized by congenital microcephaly and is caused by the mutation in the abnormal spindle-like, microcephaly-associated (ASPM) gene. This study aimed to demonstrate a correlation between radiological and pathological analyses in evaluating postnatal brain development using MCPH5-model mice, ASPM ortholog (Aspm) knockout (KO) mice. In vivo MRI was performed at two time points (postnatal 3 weeks; P3W and P10W) and complementary histopathological analyses of brains were done at P5W and P13W. In the MRI analysis, Aspm KO mice showed significantly decreased brain sizes (average 8.6% difference) with larger ventricles (average 136.4% difference) at both time points. Voxel-based statistics showed that the fractional anisotropy (FA) values were significantly lower in Aspm KO mice in both the cortex and white matter at both time points. Developmental changes in the FA values were less remarkable in the Aspm KO mice, compared with the controls. Histometric analyses revealed that the ratios of the horizontal to the vertical neurites were significantly higher in cortical layers IV, V and VI, with a remarkable increase according to maturation at P13W in the control mice (average 12.7% difference between control and KO), whereas the ratio in layer VI decreased at P13W in the KO mice. The myelin basic protein positive ratio in the white matter significantly decreased in Aspm KO mice at P5W. These results suggest that temporal FA changes are closely correlated with pathological findings such as abnormal neurite outgrowth and differentiation, which may be applicable for analyzing diseased human brain development., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood., Objective: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model., Methods: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry., Results: PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia., Conclusion: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.

Functional neuroimaging, applied to pre-clinical models of chronic pain, offers unique advantages in the drive to discover new treatments for this prevalent and oppressive condition. The high spatial and temporal resolution of fMRI affords detailed mapping of regional pharmacodynamics that underlie mechanisms of pain suppression by new analgesics. Despite evidence supporting the translational relevance of this approach, relatively few studies have investigated fMRI abnormalities in rodent models of chronic pain. In this study, we used fMRI to map the BOLD response in a recently developed putative rat model of fibromyalgia to innocuous and acute nociceptive stimuli by applying a step-wise graded electrical forepaw stimulation paradigm, with comparison to healthy controls. We observed discriminatory functional signatures (p < 0.001) to 2 mA electrical forepaw stimulation, found to be innocuous in the control group. As such, this translational approach provides sensitive and quantitative neural correlates of the underlying chronic disease. The regional patterns of functional augmentation were found to be concordant with previous studies of nociception in the anaesthetised rat brain, supporting the specificity of this approach in the study of altered central pain processing in reserpine induced myalgia. The methodology introduced in this work represents a novel platform for emerging treatment evaluation in highly experimentally controlled conditions., Competing Interests: A.F. and M.T. receive their salary from their employer, Astellas Pharma Inc. The authors, J.W., S.S., T.S. and I.A., have no conflicts of interest to declare.

Chemogenetic manipulation of neuronal activities has been enabled by a designer receptor (designer receptor exclusively activated by designer drugs, DREADD) that is activated exclusively by clozapine-N-oxide (CNO). Here, we applied CNO as a functional reporter probe to positron emission tomography (PET) of DREADD in living brains. Mutant human M4 DREADD (hM4Di) expressed in transgenic (Tg) mouse neurons was visualized by PET with microdose [ 11 C]CNO. Deactivation of DREADD-expressing neurons in these mice by nonradioactive CNO at a pharmacological dose could also be captured by arterial spin labeling MRI (ASL-MRI). Neural progenitors derived from hM4Di Tg-induced pluripotent stem cells were then implanted into WT mouse brains and neuronal differentiation of the grafts could be imaged by [ 11 C]CNO-PET. Finally, ASL-MRI captured chemogenetic functional manipulation of the graft neurons. Our data provide the first demonstration of multimodal molecular/functional imaging of cells expressing a functional gene reporter in the brain, which would be translatable to humans for therapeutic gene transfers and cell replacements., Significance Statement: The present work provides the first successful demonstration of in vivo positron emission tomographic (PET) visualization of a chemogenetic designer receptor (designer receptor exclusively activated by designer drugs, DREADD) expressed in living brains. This technology has been applied to longitudinal PET reporter imaging of neuronal grafts differentiated from induced pluripotent stem cells. Differentiated from currently used reporter genes for neuroimaging, DREADD has also been available for functional manipulation of target cells, which could be visualized by functional magnetic resonance imaging (fMRI) in a real-time manner. Multimodal imaging with PET/fMRI enables the visualization of the differentiation of iPSC-derived neural progenitors into mature neurons and DREADD-mediated functional manipulation along the time course of the graft and is accordingly capable of fortifying the utility of stem cells in cell replacement therapies., (Copyright © 2016 the authors 0270-6474/16/3611545-15$15.00/0.)

Purpose: The detailed in vivo T1 -weighted contrasting abilities of nitroxyl contrast agents, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, in mouse brain were investigated., Methods: Distribution and pharmacokinetics of five types of five-membered-ring nitroxyl radical compound were compared using T1 -weighted MRI., Results: The blood-brain barrier (BBB) -impermeable 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP) could not be distributed in the brain. The slightly lipophilic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP) showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl (MCP) had good initial uniform distribution in the brain and showed typical 2-phase signal decay profiles. A brain-seeking nitroxyl probe, acetoxymethyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl-3-carboxylate (CxP-AM), showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 4-(N-methyl piperidine)-2,2,5,5-tetramethylpyrroline-N-oxyl (23c) was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay., Conclusion: Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool. Magn Reson Med 76:935-945, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Purpose: To evaluate the neurochemical changes associated with hypomyelination, especially to clarify whether increased total N-acetylaspartate (tNAA) with decreased choline (Cho) observed in the thalamus of msd mice with the plp1 mutation is a common finding for hypomyelinating disorders., Materials and Methods: We performed magnetic resonance imaging (MRI) and proton MR spectroscopy ((1) H-MRS) of the thalamus and cortex of postnatal 12-week shiverer mice devoid of myelin basic protein (mbp), heterozygous and wild-type mice with a 7.0T magnet. Luxol Fast Blue staining and immunohistochemical analysis with anti-Mbp, Gfap, Olig2, and NeuN antibodies were also performed., Results: In the thalamus, decreased Cho and normal tNAA were observed in shiverer mice. In the cortex, tNAA, Cho, and glutamate were decreased in shiverer mice. Histological and immunohistochemical analysis of shiverer mice brains revealed hypomyelination in the thalamus, white matter, and cortex; astrogliosis and an increased number of total oligodendrocytes in the white matter; and a decreased number of neurons in the cortex., Conclusion: The reduction of Cho on (1) H-MRS might be a common marker for hypomyelinating disorders. A normal tNAA level in the thalamus of shiverer mice might be explained by the presence of mature oligodendrocytes, which enable neuron-to-oligodendrocyte NAA transport or NAA catabolism., (Copyright © 2013 Wiley Periodicals, Inc.)

Accumulation of intracellular tau fibrils has been the focus of research on the mechanisms of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we have developed a class of tau ligands, phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs), for visualizing diverse tau inclusions in brains of living patients with AD or non-AD tauopathies and animal models of these disorders. In vivo optical and positron emission tomographic (PET) imaging of a transgenic mouse model demonstrated sensitive detection of tau inclusions by PBBs. A pyridinated PBB, [(11)C]PBB3, was next applied in a clinical PET study, and its robust signal in the AD hippocampus wherein tau pathology is enriched contrasted strikingly with that of a senile plaque radioligand, [(11)C]Pittsburgh Compound-B ([(11)C]PIB). [(11)C]PBB3-PET data were also consistent with the spreading of tau pathology with AD progression. Furthermore, increased [(11)C]PBB3 signals were found in a corticobasal syndrome patient negative for [(11)C]PIB-PET., (Copyright © 2013 Elsevier Inc. All rights reserved.)

As the oscillating gradient spin-echo sequence has shown promise as a means to probe tissue microstructure, it was applied here to diffusion-tensor imaging of in vivo rat brain. The apparent diffusion tensor (ADT) was estimated for motion-probing gradient (MPG) frequencies in the range 33.3-133.3 Hz, and regions-of-interest (ROIs) in the corpus callosum (CC), visual cortex (VC), cerebellar white matter (CBWM) and cerebellar grey matter (CBGM) were selected for detailed analysis. There were substantial, approximately linear changes to the ADT with increasing MPG frequency for all four ROIs. All ROIs showed clear increases in mean diffusivity. CBWM had a substantial decrease in fractional anisotropy, whereas the CC and VC had minor increases of the same parameter. All eigenvalues of the ADT tended to increase with frequency for the CBWM, CBGM and VC, but only the principal eigenvalue increased strongly for the CC. On the other hand, there was no evidence that the orientation of the principal eigenvector varied systematically with MPG frequency for any of the ROIs. The relationship between the behaviour of the eigenvalues and the behaviours of the mean diffusivity and fractional anisotropy is investigated in detail. Pixelwise linear fits to the MD from individual animals found elevated changes across the cerebellum. The data acquired for this work encompassed a range of effective diffusion-times from 7.5 ms down to 1.875 ms, and some ideas on how the results might be used to extract quantitative information about brain tissue microstructure are discussed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aberrant expression of ferritin, a major iron-binding protein, has shown to be involved in neurodegenerative diseases. In this study, we generated transgenic (Tg) mice of human ferritin heavy chain (FTH) gene and investigated the effects of ferritin overexpression in FTH-Tg brain by (1)H-MRI and (1)H-MRS. The mice displayed no apparent neurological symptoms, and no specific morphological and T(2) alterations were found in the brain by MRI, and not even by histological studies. (1)H-MRS, however, revealed that some metabolic markers were significantly altered in FTH-Tg brains compared to wild-type control brains, such as decreases in myo-inositol and glutamine, and an increase in lactate. Our present studies suggested that despite the absence of neurological, morphological, T(2), and histological signatures, brain metabolisms were significantly affected in FTH-Tg mice. This study also highlights the usefulness of (1)H-MRS in the analysis of transgenic mouse models., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Our purpose was to noninvasively assess formation of the microvasculature, blood-brain barrier (BBB) and blood-CSF barrier formation of prenatal X-ray-induced CNS abnormalities using quantitative MRI. Eight pregnant female Sprague-Dawley rats were divided into two groups consisting of control and X-irradiated animals. After birth, 20 neonatal male rats were divided into four groups of five rats. To evaluate the development of the BBB, changes in T(1) induced by Gd-DTPA were compared quantitatively in normal and prenatally irradiated animals in the formative period 1 to 2 weeks after birth. To assess the abnormalities of the microvasculature, quantitative perfusion MRI and MR angiography were also used. Histology was also performed to evaluate the BBB (albumin) and vascular endothelial cells (laminin). Decreased cerebral blood flow (CBF) and angioarchitectonic abnormalities were observed in the prenatally irradiated rats. However, abnormalities of the BBB and blood-CSF barrier were not observed using Gd-enhanced MRI and albumin staining. Quantitative perfusion MRI, MR angiography and Gd-enhanced T(1) mapping are useful for assessing CNS disturbance after prenatal exposure to radiation. These techniques provide important diagnostic information for assessing the condition of patients during the early stages of life after accidental or unavoidable prenatal exposure to radiation.

Reactive astrogliosis occurs after diverse central nervous system (CNS) insults. While astrogliosis provides protection against inflammation, it is also obstructive in the progress of neuranagenesis after CNS insults. Thus, a method that enables in vivo visualization and tissue characterization for gliosis would be invaluable for studies of CNS insults and corresponding treatments. Manganese has proven to be a useful MRI contrast agent that enters cells via Ca(2+) channels and has been applied to manganese-enhanced MRI (MEMRI) for neuronal functional mapping. This study investigated whether MEMRI can detect astrogliosis after focal ischemia in vivo. Rats were divided into groups according to the number of days after either transient middle cerebral artery occlusion or a sham. Ring- or crescent-shaped enhancement of MEMRI corresponded to the GFAP-positive astroglia observed in the peripheral region of the ischemic core 11 days after middle cerebral artery occlusion. This indicates that MEMRI enhancement predominantly reflects reactive astrogliosis after stroke., (Copyright 2009 Elsevier Inc. All rights reserved.)

The present study describes a novel nonradioactive methodology for in vivo noninvasive, real-time imaging of blood-brain barrier (BBB) permeability for conventional drugs, using nitroxyl radicals as spin-labels and magnetic resonance imaging (MRI). Two TEMPO-labeled analogues (SLENU and SLCNUgly) of the anticancer drug lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] were synthesized, using a substitution of the cyclohexyl part with nitroxyl radical. Nonmodified nitroxyl radical TEMPOL was used for comparison. The nitroxyl derivatives were injected intravenously in healthy mice via the tail vein, and MR imaging of the brain was performed on a 7.0 T MRI. The MRI signal dynamic of SLENU and SLCNUgly followed the same kinetics as nonmodified TEMPO radical. SLENU and SLCNUgly were rapidly transported and randomly distributed in the brain tissue, which indicated that the exchange of cyclohexyl part of lomustine with TEMPO radical did not suppress the permeability of the anticancer drug for BBB. The selected nitroxyl derivatives possessed different hydrophobicity, cell permeabilization ability, and blood clearance. Based on these differences, we investigated the relationship betweenthe structure of nitroxyl derivatives, their half-life in the circulation, and their MRI signal dynamic in the brain. This information was important for estimation of the merits and demerits of the described methodology and finding pathways for overcoming the restrictions.

In the present study, we describe a multimodal QD probe with combined fluorescent and paramagnetic properties, based on silica-shelled single QD micelles with incorporated paramagnetic substances [tris(2,2,6,6-tetramethyl-3,5-heptanedionate)/gadolinium] into the micelle and/or silica coat. The probe was characterized with high photoluminescence quantum yield and good positive MRI contrast, low cytotoxicity, and easy intracellular delivery in viable cells. The intravenous administration of the probe in experimental animals did not affect significantly the physiological parameters and microcirculation (e.g., heart rate, blood pressure, diameter and shape of blood vessels), which makes it appropriate for tracing of blood circulation and in vivo multimodal imaging using fluorescent confocal microscopy, two-photon microscopy, and MRI.

Manganese-enhanced MRI (MEMRI) is being increasingly used for MRI in animals due to the unique T1 contrast that is sensitive to a number of biological processes. Three specific uses of MEMRI have been demonstrated: to visualize activity in the brain and the heart; to trace neuronal specific connections in the brain; and to enhance the brain cytoarchitecture after a systemic dose. Based on an ever-growing number of applications, MEMRI is proving useful as a new molecular imaging method to visualize functional neural circuits and anatomy as well as function in the brain in vivo. Paramount to the successful application of MEMRI is the ability to deliver Mn2+ to the site of interest at an appropriate dose and in a time-efficient manner. A major drawback to the use of Mn2+ as a contrast agent is its cellular toxicity. Therefore, it is critical to use as low a dose as possible. In the present work the different approaches to MEMRI are reviewed from a practical standpoint. Emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn2+ to the target areas of interest., (Copyright 2004 John Wiley & Sons, Ltd.)

Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced., (Copyright 2004 John Wiley & Sons, Ltd.)

Visualizing brain anatomy in vivo could provide insight into normal and pathophysiology. Here it is demonstrated that neuroarchitecture can be detected in the rodent brain using MRI after systemic MnCl2. Administration of MnCl2 leads to rapid T1 enhancement in the choroid plexus and circumventricular organs, which spreads to the CSF space in ventricles and periventricular tissue. After 1 day, there was MRI enhancement throughout the brain with high intensity in the pituitary, olfactory bulb, cortex, basal forebrain, hippocampus, basal ganglia, hypothalamus, amygdala, and cerebellum. Contrast obtained enabled visualization of specific features of neuroarchitecture. The arrowhead structure of the dentate gyrus as well as the CA1-CA3 region of the hippocampus and layers in cortex, cerebellum, as well as the olfactory bulb could be readily observed. Preliminary assignments of olfactory bulb layers, cortical layers in frontal and somatosensory cortex, and cerebellum were made. Systemic MnCl2 leads to MRI visualization of neuroarchitecture nondestructively., (Copyright 2004 Elsevier Inc.)

Mismatch between diffusion- and perfusion-weighted MRI was used to indicate a treatable area following focal ischemia, called the penumbra. Activity-induced manganese contrast MRI has been reported as a new visualization method for neural activation using manganese ions as a depolarization-dependent contrast agent. It is well known that energy failure induced by cerebral ischemia produces anoxic depolarization. The purpose of this study was to detect manganese accumulation caused by permanent middle cerebral artery occlusion (MCAO) of rat brain and to compare regional differences between manganese accumulation and decreased apparent diffusion coefficient (ADC). The ratios of signal intensity of manganese-enhanced MRI in the ipsilateral cortex to that in the contralateral cortex were 171.0 +/- 17.5% in MCAO group and 108.4 +/- 13.2% in the sham group. In addition, the enhanced region was much smaller than the area which was detected as having a reduced ADC., (Copyright 2003 Wiley-Liss, Inc.)

Activity-induced manganese-dependent contrast (AIM) MRI is a hemodynamic-independent functional MRI method that used manganese ion as an MR-detectable contrast agent. In AIM, MnCl(2) is infused intra-arterially after the blood-brain barrier (BBB) is opened with a hyperosmolar agent. Upon functional stimulation of the brain, Mn(2+) accumulates in the active region(s) by entering active cells through voltage-gated Ca(2+) channels, causing local signal increases in T(1)-weighted images. The contrast of AIM MRI depends strongly on the depth of anesthesia, and the low levels used in somatosensory stimulation studies can lead to significant nonspecific accumulation of manganese ion throughout the brain. The purpose of this study was to produce an AIM functional map of somatosensory stimulation, which separates the stimulation-specific signal increase from the nonspecific activation due to light anesthesia. A dynamic AIM (DAIM) paradigm was developed, which used sequential MR scans during MnCl(2) infusion, prior to and following functional stimulation of the brain. Stimulation-specific functional maps were produced using time-course analysis. The new method was tested during glutamate administration and electric stimulation of the rat forepaw. It was shown that DAIM maps are better confined to the specific region of brain activated by somatosensory stimulation as compared to AIM MRI., (Copyright 2002 Wiley-Liss, Inc.)

Background: The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer's disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer's beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg).Methods: Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice.Results: TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy.Conclusions: These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy. [ABSTRACT FROM AUTHOR]

The aim of this study was to spatio-temporally clarify gross structural changes in the forebrain of cynomolgus monkey fetuses using 7-tesla magnetic resonance imaging (MRI). T1-weighted coronal, horizontal, and sagittal MR slices of fixed left cerebral hemispheres were obtained from one male fetus at embryonic days (EDs) 70–150. The timetable for fetal sulcation by MRI was in good agreement with that by gross observations, with a lag time of 10–30 days. A difference in detectability of some sulci seemed to be associated with the length, depth, width, and location of the sulci. Furthermore, MRI clarified the embryonic days of the emergence of the callosal (ED 70) and circular (ED 90) sulci, which remained unpredictable under gross observations. Also made visible by the present MRI were subcortical structures of the forebrain such as the caudate nucleus, globus pallidus, putamen, major subdivisions of the thalamus, and hippocampal formation. Their adult-like features were formed by ED 100, corresponding to the onset of a signal enhancement in the gray matter, which reflects neuronal maturation. The results reveal a highly reproducible level of gross structural changes in the forebrain using a high spatial 7-tesla MRI. The present MRI study clarified some changes that are difficult to demonstrate nondestructively using only gross observations, for example, the development of cerebral sulci located on the deep portions of the cortex, as well as cortical and subcortical neuronal maturation. [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to characterize cerebral morphology in young adult ferrets and its sexual dimorphism using high-field MRI and MRI-based morphometry. Ex vivo short TR/TE (typical T1-weighted parameter setting for conventional MRI) and T2W (long TR/TE) MRI with high spatial resolution at 7-tesla could visualize major subcortical and archicortical structures, i.e., the caudate nucleus, lentiform nucleus, amygdala and hippocampus. In particular, laminar organization of the olfactory bulb was identifiable by short TR/TE-MRI. The primary and secondary sulci observable in the adult ferret were distinguishable on either short TR/TE- or T2W-MRI, and the cortical surface morphology was reproduced well by 3D-rendered images obtained by short TR/TE-MRI. The cerebrum had a significantly lower volume in females than in males, which was attributed to region-specific volume reduction in the cerebral cortex and subcortical white matter in females. A sexual difference was also detected, manifested by an overall reduction in normalized signal ratios of short TR/TE-MRI in all cerebral structures examined in females than in males. On the other hand, an alternating array of higher and lower short TR/TE-MRI intensity transverse zones throughout the cortex, which was reminiscent of the functional cortical areas, was revealed by maximum intensity projection (MIP) in 3D. The normalized signal ratio of short TR/TE-MRI, but not T2W-MRI in the cortex, was negatively correlated with the density of myelin-basic protein immunoreactive fibers (males, r=−0.440; females, r=−0.481). The present results suggest that sexual differences in the adult ferret cerebrum are characterized by reduced volumes of the cerebral cortex and subcortical white matter in females, and by overall reductions in physiochemical characteristics, as obtained by short TR/TE-MRI, in females. It should be noted that short TR/TE-MRI-based MIP delineated functional cortical areas related to myeloarchitecture in 3D. Such an approach makes possible conventional investigation of the functional organization of the cerebral cortex and its abnormalities using high-field MRI. [Copyright &y& Elsevier]

Abstract: Changes in manganese-enhanced MRI (MEMRI) contrast across the rodent somatosensory cortex were compared to the cortical laminae as identified by tissue histology and administration of an anatomical tracer to cortex and thalamus. Across the cortical thickness, MEMRI signal intensity was low in layer I, increased in layer II, decreased in layer III until mid-layer IV, and increased again, peaking in layer V, before decreasing through layer VI. The reeler mouse mutant was used to confirm that the cortical alternation in MEMRI contrast was related to laminar architecture. Unlike in wild-type mice, the reeler cortex showed no appreciable changes in MEMRI signal, consistent with absence of cortical laminae in histological slides. The tract tracing ability of MEMRI was used to further confirm assignments and demonstrate laminar specificity. Twelve to 16h after stereotaxic injections of MnCl2 to the ventroposterior thalamic nuclei, an overall increase in signal intensity was detected in primary somatosensory cortex compared to other brain regions. Maximum intensity projection images revealed a distinctly bright stripe located 600–700μm below the pial surface, in layer IV. The data show that both systemic and tract tracing forms of MEMRI are useful for studying laminar architecture in the brain. [Copyright &y& Elsevier]